External adhesive preparation containing steroids

ABSTRACT

An external adhesive preparation comprising a steroid for treatment of skin diseases in admixture with an adhesive gel base comprising as essential components a water-soluble high molecular weight compound, water and a water-retaining agent. The external adhesive preparation is useful for treatment of skin diseases by applying the preparation spread on a soft support directly to diseased parts on the skin, thereby administering the contained steroid to the skin.

This application is a continuation of application Ser. No. 07/189,313filed on Apr. 20, 1988, now abandoned.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an external adhesive preparationcontaining steroids. More specifically, the present invention relates toan external adhesive preparation containing steroids which is obtainedby incorporating a steroid useful for the treatment of skin diseasesinto an adhesive gel base comprising as essential components awater-soluble high molecular weight compound, water and awater-retaining agent and spreading the resulting composition onto asoft support, said preparation being directly applied to diseased partson the skin so that the contained steroids are administered to the skinfor treatment of the diseases.

PRIOR ART

Hitherto, for the treatment of allergic skin diseases such as eczema,hives, children's strophulus, contoured exudative erythema, Behcet'ssyndrome, keratodermia palmaris, psoriasis and the like, there have beenused oral preparations, injections, external preparations and the likecontaining cortisone etc. as an active component.

However, these preparations have some side effect or inconvenience inusage. For example, in case of oral preparations, there is a fear offorgetting taking or an excess administration. In case of injections,patients suffer from pain or stress when administering drugs and furtherit is difficult to be administered by the patients themselves. Externalpreparations such as ointments or lotions not only stain clothes and thelike but also are hardly administered in a fixed-amount. Further, incase of external preparations, patients are forced to be given by aphysical stimulus to the diseased parts which are most accompanied withurtication and this stimulus sometimes makes worse symptoms. Therefore,the external preparations are not necessarily suitable. For the purposeof obviating the above-mentioned disadvantages, there have beendeveloped tapes which are produced by incorporating a steroid into apressure sensitive adhesive comprising a natural gum or a copolymer ofacrylic acid ester - acrylic acid. These tapes are more advantageousthan conventional external preparations in many respects, i.e. they mayhave an effect similar to occlusive dressing technique by applying themto diseased parts, and they are more easily handled in such a treatmentmethod. However, the application of these tapes to diseased partsinduces occasionally contact dermatitis caused by the adhesive itself,folliculitis caused by bacteria etc. on the skin, or cutaneousinflammation due to stimulus of sweat glands. Furthermore, these tapesare still unsatisfactory in that when these tapes are removed, diseasedparts are rather injured or keratin is peeled off, and therefore notonly is it difficult to apply them successively, but also symptoms maybe made worse.

OBJECT OF THE INVENTION

As a result of the present inventors' intensive study to obviate defectsof these tapes and the like, it has been found that an excellentadhesive preparation, without defects as seen in the conventional tapes,could be obtained by incorporating a steroid as the active ingredientinto an adhesive base comprising as essential components a water-solublehigh molecular weight compound, water and a water-retaining agent, andspreading this base on a soft support, and thus, the present inventionhas been accomplished. That is, the present invention provides anexternal adhesive preparation which is prepared by incorporating asteroid into an adhesive gel base comprising as essential components awater-soluble high molecular weight compound, water and awater-retaining agent.

BRIEF EXPLANATION OF THE DRAWING

FIG. 1 is a graph showing a cumulative release rate of active agent asto the adhesive preparations of the present invention prepared inExamples 1 and 2 and tapes prepared in Comparative Examples 1 to 3.

DISCLOSURE OF THE INVENTION

The water-soluble high molecular weight compound employed in theexternal adhesive preparations of the present invention includesgelatin, agar, alginic acid, mannan, carboxymethylcellulose,methylcellulose, polyvinyl alcohol, polyacrylic acid, gum arabic, andthe like, as well as metal salts thereof and cross-linked productsthereof with organic or inorganic cross-linking agents, and the like.These water-soluble high molecular weight compounds are employed aloneor in combination of two or more thereof depending on properties ofother materials used in the adhesive gel base and are mixed with the gelbase in an amount of from 0.1 to 30 w/w %, preferably from 0.5 to 15 w/w%.

A water-retaining agent includes polyhydric alcohols such aspolyethylene glycol, glycerol, sorbitol, maltitol, propylene glycol and1,3-butanediol. These are employed alone or in combination of two ormore thereof and are mixed with the gel base in an amount of from 5 to60 w/w %, preferably from 10 to 50 w/w %. Also there may be employedhighly absorptive high molecular weight compounds, such as starch -acrylonitrile graft copolymer, starch-acrylic acid graft copolymer,starch - styrenesulfonic acid graft copolymer, starch - vinylsulfonicacid graft copolymer, cellulose - acrylonitrile graft copolymer,cellulose - styrenesulfonic acid graft copolymer, a cross-linked productof carboxymethylcellulose, a cross-linked product of polyvinyl alcohol,a saponification product of acrylic acid - vinyl acetate, a cross-linkedproduct of polyacrylate, a saponification product of polyacrylonitrilicpolymer and a cross-linked product of polyethylene glycol diacrylate.These are employed in an amount of from 0.01 to 10.0 w/w %, preferablyfrom 0.05 to 7.0 w/w %.

One of the characteristics of the adhesive gel base employed in thepresent invention is that it contains water, thereby enhancing anabsorption of steroids as an active component. The water content is inthe range of from 10 to 70 w/w %, preferably from 20 to 50 w/w %.

The steroids which are an active component of the external adhesivepreparations of the present invention include, for example, deprodonepropionate, fluocinolone acetonide, triamcinolone acetonide,dexamethasone, methylprednisolone, prednisolone, hydrocortisone,paramethasone, betamethasone, betamethasone sodium phosphate,dexamethasone acetate, cortisone acetate, hydrocortisone acetate,methylprednisolone acetate, clobetasol propionate, hydrocortisonebutyrate, fluocinonide, fluorometholone, fludroxycortide, flumethasonepivalate, beclomethasone propionate, betamethasone valerate,methylprednisolone acetate and the like. These steroids- areincorporated into the adhesive gel base in an amount of from 0.001 to 1w/w %, preferably from 0.005 to 0.5 w/w %, more preferably from 0.01 to0.25 w/w %.

In order to improve a solubility or a dispersibility of the abovesteroids in water, the gel base may contain oil components, surfactantsand the like such as crotamiton, benzyl alcohol, isopropyl myristate,ethylene glycol, diethyl sebacate-2-ethyl-5-pyrrolidone.

Further, if necessary, known stabilizing agents, antioxidants, pHcontrolling agents or inorganic fillers may also be added. Thestabilizing agents and antioxidants include, for example, disodiumedetate, tetrasodium edetate, sodium metabisulfite,dibutylhydroxytoluene (BHT), butylhydroxyanisol (BHA), ascorbic acid,sodium ascorbate, erythorbic acid, sodium erythorbate, sodium sulfite,d-α-tocopherol, tocopherol acetate, guaiacum resin, nordihydroguaiareticacid, propyl gallate and the like, which may be used alone or incombination of two or more thereof. These are mixed usually in an amountof from 0.005 to 1.0 w/w %, preferably from 0.01 to 0.5 w/w %.

A support employed in the present invention is preferably such a softone and being able to follow a movement of a human body, and includesvarious woven fabrics, non-woven fabrics, flannels and the like. Theexternal adhesive preparations of the present invention are expected tohave an effect such as that associated with occlusive dressingtechniques since the adhesive gel base layer is a continuous phase.However, when more powerful effects than that of occlusive dressingtechniques are desired, the above-mentioned support may be laminated byethylene vinyl acetate, polyethylene, polyvinyl chloride, polyurethaneand the like.

The external adhesive preparation of the present invention has less sideeffects such as cutaneous inflammation and further less injury ofdiseased parts or peeling off of keratin when the preparations areremoved as compared with the conventional tapes, and hence, the presentpreparation can be used successively. Moreover, when the externaladhesive preparation of the present invention is applied to diseasedparts on the skin, not only is an effect of occlusive dressingtechniques expected, as in the case of conventional tapes, but also moreexcellent treatment effects can be obtained through increased absorptionof the main component steroid, which is induced by an active hydrationof the keratin layer owing to water contained in the external adhesivepreparation of the present invention.

In order to exhibit the medical effects, by applying the externaladhesive preparation to cutaneous diseased parts, it is necessary thatthe active ingredient is released from the base and transferred into thecutaneous diseased part. It is known that an affinity between the activeingredient and the base is related to the above and has an influence onthe medical effects. The affinity is influenced by various factors suchas the solubility, the diffusion coefficient, and the thermodynamicactivity, and the like of the base or active agent in the base. In caseof the external adhesive preparation of the present invention, thesefactors are controllable by varying a combination of the base componentsthus enabling one to adjust an optimum concentration of each activeingredient, and thereby, desired treatment effects can be moreeffectively exhibited as compared with the other conventionalpreparations.

THE BEST MODE FOR WORKING THE INVENTION

The present invention is more specifically illustrated by the followingExamples and Experiments. In the Examples, "part" means a part byweight.

Example 1

A mixture of 31 parts of water, 5.0 parts of gelatin, 0.1 part of methylp-hydroxybenzoate, 0.2 part of citric acid, 0.2 part of deprodonepropionate, 1.0 part of crotamiton, 20 parts of sorbitol, 30 parts ofglycerol and 4.0 parts of polyacrylic acid is stirred with heating in akneader to give a solution, and thereto is added a solution of 0.5 partof aluminum potassium sulfate in 8 parts of water, and the mixture isstirred well to give an adhesive gel base. This adhesive gel base isapplied and spread on a release paper in an amount of 200 g/m² in aconventional manner, and then transferred to polyurethane-laminatednon-woven fabric made of rayon, which is cut in a desired size to givean external adhesive preparation containing 40 μg/cm² of deprodonepropionate.

Example 2

A mixture of 25 parts of water, 10 parts of polyacrylic acid, 5 parts ofzinc white, 6 parts of polyvinyl alcohol, 3.0 parts of benzyl alcohol,0.2 part of deprodone propionate, 0.1 part of propyl p-hydroxybenzoate,8.0 parts of carboxymethylcellulose sodium, 20 parts of glycerol and 20parts of sorbitol is dissolved in a kneader in the same manner as inExample 1, and thereto is added a solution of 0.2 part ofdihydroxyaluminum aminoacetate in 2.5 parts of water, and the mixture iswell stirred to give an adhesive gel base. Using this base, theprocedure of Example 1 is repeated to give an external adhesivepreparation containing 40 μg/cm² of deprodone propionate.

Example 3

Except that 0.025 part of deprodone propionate is employed, theprocedure of Example 1 is repeated to give an external adhesivepreparation containing 5 μg/cm² of deprodone propionate.

Example 4

Except that 0.05 part of deprodone propionate is employed, the procedureof Example 1 is repeated to give an external adhesive preparationcontaining 10 μg/cm² of deprodone propionate.

Example 5

Except that 0.1 part of deprodone propionate is employed, the procedureof Example 1 is repeated to give an external adhesive preparationcontaining 20 μg/cm² of deprodone propionate.

Example 6

Except that 0.4 part of deprodone propionate is employed, the procedureof Example 1 is repeated to give an external adhesive preparationcontaining 80 μg/cm² of deprodone propionate.

Comparative Example 1

A four-necked flask is charged with a mixture of 7.0 parts of acrylicacid, 68 parts of 2-ethylhexyl acrylate, 25 parts of vinyl acetate, 0.2part of azobisisobutyronitrile and 150 parts of ethyl acetate undernitrogen. The mixture is stirred with heating at 65° C.-70° C. toconduct polymerization to give an acrylic adhesive agent having 40% of asolid content. To 99.6 parts (in solid content) of the adhesive agent isadded 0.4 part of deprodone propionate, and the mixture is applied to inan amount of 100 g/m² (in dry state) in a conventional manner, which islaminated on polyethylene film to give an acrylic adhesive tapecontaining 40 μg/cm² of deprodone propionate.

Comparative Example 2

Fifty parts of raw rubber is dissolved in 203 parts of toluene andtherein are dissolved with stirring 10 parts of polybutene, 38 parts ofester gum and 2.0 parts of dibutylhydroxytoluene to give a natural gumadhesive agent having 33% of a solid content. Then, after 0.4 part ofdeprodone propionate is added to 99.6 parts (in solid content) of theadhesive agent, the procedure of Comparative Example 1 is repeated togive a natural gum adhesive tape containing 40 μg/cm² of deprodonepropionate.

Comparative Example 3

A mixture of 29 parts of styrene-isoprene-styrene copolymer, 47 parts ofan alicyclic saturated hydrocarbon petroleum resin, 10 parts of a liquidpolyisoprene rubber, 12.6 parts of a liquid paraffin and 1.0 part of anantioxidant is dissolved with heating at 160° C. in a kneader. Afterstirring, the mixture is cooled to 120° C. and thereto is added 0.4 partof deprodone propionate, and the mixture is applied to a release paperwith a coator in an amount of 100 g/m². After cooling, the mixture istransferred to a polyethylene vinyl acetate film, which is cut in adesired size to give a hot-melt type adhesive tape containing 40 μg/cm²of deprodone propionate.

Experiment 1

The vasoconstrictor test was carried out as to the adhesive preparationsprepared in Examples 1-6, the tapes prepared in Comparative Examples1-3, a commercially available acrylic adhesive tape containing 4 μg/cm²of fludroxycortide and a commercially available acrylic adhesive tapecontaining 8 μg/cm² of fluocinolone acetonide to compare effects ofthese preparations or tapes.

These adhesive preparations and tapes containing steroids, and further,blank adhesive preparations and tapes which were prepared by removingdeprodone propionate from the adhesive preparations in Examples 1-2 andthe tapes in Comparative Examples 1-3 (hereinafter, referred to merelyas blank of Example 1 and the like) were punched in a circular form of15 mm diameter to give test samples. The samples were adhered to backsof 20 healthy adult men. Application periods were 30 minutes, 1 hour, 2hours and 4 hours. After removal, the applied portions were wiped withslightly warm water. Two hours later a degree of the vasoconstrictoractivity was evaluated. The experiment was carried out by a double blindtest.

The results are shown in Table 1. The figures in the table are % of anumber having the vasoconstrictor activity in the 20 volunteers.

                  TABLE 1                                                         ______________________________________                                        Vasoconstrictor test                                                          Sample   30 min.   1 hour    2 hours 4 hours                                  name     application                                                                             application                                                                             application                                                                           application                              ______________________________________                                        Example 1                                                                              75        85        100     100                                      Example 2                                                                              60        90        95      100                                      Example 3                                                                              5         15        50      55                                       Example 4                                                                              10        30        65      80                                       Example 5                                                                              30        55        75      100                                      Example 6                                                                              95        100       100     100                                      Comp. Ex. 1                                                                            10        55        70      90                                       Comp. Ex. 2                                                                            15        50        75      90                                       Comp. Ex. 3                                                                            30        60        85      100                                      Commercial                                                                             5         25        55      60                                       product 1                                                                     Commercial                                                                             5         15        40      65                                       product 2                                                                     Example 1                                                                              5          5         0       5                                       Example 2                                                                              5          0         5       5                                       Comp. Ex. 1                                                                            0          5         0       0                                       Comp. Ex. 2                                                                            0          0         0       0                                       Comp. Ex. 3                                                                            0          0         5       0                                       ______________________________________                                    

Experiment 2

Employing Franz Diffusion Cell (manufactured by CROWN GLASS Co. Inc.),active agent release patterns of each adhesive preparation and tape wereevaluated. The test samples were punched into 15 mm diameter and adheredto silicone membrane and the amount of deprodone propionate transferredinto phosphate buffer of pH 7.4 was measured by HPLC. The measurementwas carried out over a period of 6 hours at an interval of 1 hour. Areleased amount of the active agent was calculated based on the chargedamount of the active agent and a cumulative release rate (%) (therelease amount/the charged amount ×100) was shown in graph (FIG. 1).

Experiment 3

In the case of the sample adhered for 4 hours in Experiment 1,conditions of cutaneous stimulus were observed immediately, 24 hours and48 hours after peeling off the sample, and evaluated as 0: no reaction,0.5: slight erythema, 1: erythema, 2: erythema with edema, 3: smallblister, 4: large blister. A mean strength of cutaneous stimulus wascalculated by multiplying these figures with a number showing theseconditions, which is then divided by a total number of volunteers. Theresults are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Strength of cutaneous stimulus                                                Sample      immed. after                                                                             24 hours after                                                                           48 hours after                              name        removal    removal    removal                                     ______________________________________                                        Example 1   0.075      0.100      0                                           Example 2   0.100      0.075      0                                           Example 3   0.225      0.100      0.075                                       Example 4   0.150      0.100      0                                           Example 5   0.075      0.05       0                                           Example 6   0.05       0.075      0                                           Comp. Example 1                                                                           0.25       0.125      0.050                                       Comp. Example 2                                                                           0.200      0.200      0.075                                       Comp. Example 3                                                                           0.175      0.125      0.075                                       Commercial  0.600      0.200      0.150                                       product 1                                                                     Commercial  0.525      0.225      0.100                                       product 2                                                                     Example 1   0.200      0.100      0.050                                       Example 2   0.325      0.100      0.025                                       Comp. Ex. 1 0.500      0.200      0.050                                       Comp. Ex. 2 0.575      0.100      0.025                                       Comp. Ex. 3 0.375      0.150      0.025                                       ______________________________________                                    

Example 7

A mixture of 31 parts of water, 5.0 parts of gelatin, 0.1 part of methylp-hydroxybenzoate, 0.2 part of citric acid, 0.1 part of triamcinoloneacetonide, 1.0 part of crotamiton, 20 parts of sorbitol, 30 parts ofglycerol and 4.0 parts of polyacrylic acid is stirred with heating in akneader to give a solution, and thereto is added a solution of 0.5 partof aluminum potassium sulfate in 8 parts of water, and the mixture isstirred well to give an adhesive gel base. This adhesive gel base isapplied and spread on a release paper in an amount of 200 g/m² in aconventional manner, and then transferred to a polyurethanelaminatednon-woven fabric made of rayon, which is cut in a desired size to givean external adhesive preparation containing 20 μg/cm² of triamcinoloneacetonide.

Example 8

A mixture of 25 parts of water, 10 parts of polyacrylic acid, 5 parts ofzinc white, 6 parts of polyvinyl alcohol, 3.0 parts of benzyl alcohol,1.0 part of hydrocortisone, 0.1 part of propyl p-hydroxybenzoate, 8.0parts of carboxymethylcellulose sodium, 20 parts of glycerol and 20parts of sorbitol is dissolved in a kneader in the same manner as inExample 7, and thereto is added a solution of 0.2 part ofdihydroxyaluminum aminoacetate in 2.5 parts of water, and the mixture iswell stirred to give an adhesive gel base. Using this base, theprocedure of Example 7 is repeated to give an external adhesivepreparation containing 200 μg/cm² of hydrocortisone.

Example 9

Except that 0.1 part of dexamethasone acetate is employed, the procedureof Example 7 is repeated to give an external adhesive preparationcontaining 20 μg/cm² of dexamethasone acetate.

Example 10

Except that 0.25 part of methylprednisolone is employed, the procedureof Example 7 is repeated to give an external adhesive preparationcontaining 50 μg/cm² of methylprednisolone.

Example 11

Except that 0.5 part of prednisolone is employed, the procedure ofExample 7 is repeated to give an external adhesive preparationcontaining 100 μg/cm² of prednisolone.

Example 12

Except that 0.04 part of fluocinolone acetonide is employed, theprocedure of Example 7 is repeated to give an external adhesivepreparation containing 8 μg/cm² of fluocinolone acetonide.

Experiment 4

The vasoconstrictor test was carried out as to the adhesive preparationsprepared in Examples 7-12, commercially available acrylic adhesive tapescontaining 4 μg/cm² of fludroxycortide, 8 μg/cm² of fluocinoloneacetonide and 6 μg/cm² of betamethasone valerate, respectively, tocompare effects of these preparations or tapes. These adhesivepreparations and the commercially available tapes containing steroidswere punched in a circular form of 10 mm diameter to give test samples.The samples were randomly assigned to and adhered to middle backs of 10healthy adult men. Application periods were 30 minutes, 1 hour, 2 hoursand 4 hours. The vasoconstrictor activity was evaluated 2 hours and 4hours after removal.

The results are shown in Tables 3-6. Table 3 and Table 4 show theresults of vasoconstrictor activity when evaluated 2 hours afterremoval, wherein Table 3 shows a number of positive and Table 4 shows anumber of pseudpositive or positive in 10 persons tested. Table 5 andTable 6 show the results when evaluated 4 hours after removal whereinTable 5 shows a number of positive and Table 6 shows a number ofpseud-positive or positive in 10 persons tested.

                  TABLE 3                                                         ______________________________________                                        Active ingredient                                                             Sample              conc.    Application period (h)                           name    Name        (μg/cm.sup.2)                                                                       0.5  1.0  2.0  4.0                               ______________________________________                                        Ex. 12  Fluocinolone                                                                              8        0    0    3    7                                         acetonide                                                             Ex. 7   Triamcinolone                                                                             20       0    3    5    7                                         acetonide                                                             Ex. 9   Dexamethasone                                                                             20       0    1    4    6                                         acetate                                                               Ex. 10  Methyl-     50       0    0    0    5                                         prednisolone                                                          Ex. 11  Prednisolone                                                                              100      0    0    1    5                                 Ex. 8   Hydrocortisone                                                                            200      0    0    1    0                                 Commerc.                                                                              Fludroxycortide                                                                           4        0    0    2    4                                 product 1                                                                     Commerc.                                                                              Fluocinolone                                                                              8        0    0    0    2                                 product 2                                                                             acetonide                                                             Commerc.                                                                              Betamethasone                                                                             6        0    0    1    4                                 product 3                                                                             valerate                                                              ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Active ingredient                                                             Sample              conc.    Application period (h)                           name    Name        (μg/cm.sup.2)                                                                       0.5  1.0  2.0  4.0                               ______________________________________                                        Ex. 12  Fluocinolone                                                                              8        0    1    5    9                                         acetonide                                                             Ex. 7   Triamcinolone                                                                             20       1    6    9    9                                         acetonide                                                             Ex. 9   Dexamethasone                                                                             20       1    4    6    10                                        acetate                                                               Ex. 10  Methyl-     50       0    1    6    6                                         prednisolone                                                          Ex. 11  Prednisolone                                                                              100      1    1    3    5                                 Ex. 8   Hydrocortisone                                                                            200      1    0    2    6                                 Commerc.                                                                              Fludroxycortide                                                                           4        0    2    4    10                                product 1                                                                     Commerc.                                                                              Fluocinolone                                                                              8        0    3    2    6                                 product 2                                                                             acetonide                                                             Commerc.                                                                              Betamethasone                                                                             6        1    2    6    8                                 product 3                                                                             valerate                                                              ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Active ingredient                                                             Sample              conc.    Application period (h)                           name    Name        (μg/cm.sup.2)                                                                       0.5  1.0  2.0  4.0                               ______________________________________                                        Ex. 12  Fluocinolone                                                                              8        0    1    7    10                                        acetonide                                                             Ex. 7   Triamcinolone                                                                             20       1    5    8    9                                         acetonide                                                             Ex. 9   Dexamethasone                                                                             20       0    5    8    10                                        acetate                                                               Ex. 10  Methyl-     50       0    1    2    7                                         prednisolone                                                          Ex. 11  Prednisolone                                                                              100      0    0    1    3                                 Ex. 8   Hydrocortisone                                                                            200      0    0    2    2                                 Commerc.                                                                              Fludroxycortide                                                                           4        0    0    3    7                                 product 1                                                                     Commerc.                                                                              Fluocinolone                                                                              8        0    0    1    6                                 product 2                                                                             acetonide                                                             Commerc.                                                                              Betamethasone                                                                             6        0    0    7    9                                 product 3                                                                             valerate                                                              ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Active ingredient                                                             Sample              conc.    Application period (h)                           name    Name        (μg/cm.sup.2)                                                                       0.5  1.0  2.0  4.0                               ______________________________________                                        Ex. 12  Fluocinolone                                                                              8        2    6    8    10                                        acetonide                                                             Ex. 7   Triamcinolone                                                                             20       4    8    9    10                                        acetonide                                                             Ex. 9   Dexamethasone                                                                             20       3    9    9    10                                        acetate                                                               Ex. 10  Methyl-     50       0    1    5    9                                         prednisolone                                                          Ex. 11  Prednisolone                                                                              100      1    3    4    9                                 Ex. 8   Hydrocortisone                                                                            200      0    0    6    5                                 Commerc.                                                                              Fludroxycortide                                                                           4        2    1    6    9                                 product 1                                                                     Commerc.                                                                              Fluocinolone                                                                              8        0    2    3    9                                 product 2                                                                             acetonide                                                             Commerc.                                                                              Betamethasone                                                                             6        0    3    7    9                                 product 3                                                                             valerate                                                              ______________________________________                                    

Example 13

A mixture of 35 parts of water, 1.5 part of gelatin, 1 part of urea, 0.5part of methyl benzoate, 0.25 part of d-tartaric acid, 6 parts ofpolyacrylic acid, 1 part of hydrocortisone, 0.1 part of d-α-tocopherol,14 parts of sorbitol, 1 part of crotamiton, 10 parts of glycerol, 3parts of carboxymethylcellulose sodium and 4 parts of sodiumpolyacrylate is stirred in a kneader with heating to give a solution,and thereto are added 0.55 part of dihydroxyaluminum aminoacetate and0.15 part of ascorbic acid, and further water is added so as to make atotal volume of 100 parts, followed by stirring the mixture well to givean adhesive gel. Using this base, the procedure of Example 1 is repeatedto give an external adhesive preparation containing 200 μg/cm² ofhydrocortisone.

Example 14

Except that 0.08 part of tetrasodium edetate and 0.1 part ofdexamethasone acetate are employed, the procedure of Example 13 isrepeated to give an external adhesive preparation containingdexamethasone acetate.

Example 15

Except that 0.04 part of disodium edetate, 0.15 part of sodium ascorbateand 0.25 part of Methylprednisolone, the procedure of Example 13 isrepeated to give an external adhesive preparation containingmethylprednisolone.

Example 16

Except that 0.25 part of prednisolone and 0.15 part of erythorbic acid,the procedure of Example 13 is repeated to give an external adhesivepreparation containing prednisolone.

Example 17

Except that 0.04 part of fluocinolone acetonide, 0.05 part of disodiumedetate and 0.1 part of BHT, the procedure of Example 13 is repeated togive an external adhesive preparation containing fluocinolone acetonide.

Example 18

Except that 0.1 part of triamcinolone acetonide, 0.05 part of disodiumedetate and 0.1 part of sodium metabisulfite, the procedure of Example13 is repeated to give an external adhesive preparation containingtriamcinolone acetonide.

We claim:
 1. An external adhesive preparation for the treatment of skindiseases which consists of an effective amount of a steroid in admixturewith an adhesive gel base consisting essentially of a water-soluble highmolecular weight compound, water, and a water-retaining agent,whereinsaid water-soluble high molecular weight compound iscarboxymethylcellulose, methyl cellulose, polyvinyl alcohol, polyacrylicacid, therapeutically effective metal salts thereof, or a combination ortwo or more thereof, which is contained in an amount of 0.1 to 30 w/w %in the adhesive gel base, said water-retaining agent being a polyhydricalcohol selected from the group consisting of glycerol, sorbitol,propylene glycol and 1,3-butanediol, which is contained in an amount of5 to 60 w/w % in an adhesive gel base, or said water-retaining agenthaving a highly absorptive high molecular weight compound selected fromthe group consisting of starch - acrylonitrile graft copolymer,starch-acrylic acid graft copolymer, cross-linked product of polyvinylalcohol, cross-linked product of carboxymethylcellulose, andcross-linked product of polyacrylate, which is contained in an amount of0.01 to 10.0 w/w % in the adhesive gel base, and said water beingcontained in an amount of 20 to 50 w/w % in the adhesive gel base. 2.The adhesive preparation as claimed in claim 1, wherein the amount ofthe water-soluble high molecular weight compound is in the range of from0.5 to 15 w/w % of the total preparation.
 3. The adhesive preparation asclaimed in claim 1, wherein the polyhydric alcohol as thewater-retaining agent is contained in an amount of from 10 to 50 w/w %of the total preparation.
 4. The adhesive preparation as claimed inclaim 1, wherein the highly absorptive high molecular weight compound asthe water-retaining agent is contained in an amount of from 0.05 to 7.0w/w % of the total preparation.
 5. The adhesive preparation as claimedin claim 1, wherein the steroid is contained in an amount of from 0.01to 1 w/w % of the total preparation.
 6. The adhesive preparation asclaimed in claim 1, wherein the adhesive gel base further contains anadditive which is an oil, a surfactant, a stabilizing agent, anantioxidant, a pH controlling agent or an organic filler.
 7. Theadhesive preparation according to claim 1, wherein the adhesive gel baseconsists of 0.5 to 15 w/w % of the total preparation of a water-solublehigh molecular weight compound being a combination of gelatin,carboxymethylcellulose and carboxymethylcellulose sodium salt, 20 to 50w/w % of water, and 10 to 50 w/w % of a water-retaining agent being acombination of glycerol and sorbitol.